Enantioselective Mannich‐Type Reaction Catalyzed by a Chiral Brønsted Acid

Abstract

The enantioselective Mannich-type reaction of an enolate or an enolate anion equivalent with aldimines constitutes a useful method for the preparation of chiral b-amino carbonyl compounds, which are the precursors of biologically important compounds such as b-lactams and b-amino acids. The development of chiral catalysts for the asymmetric Mannichtype reaction has attracted the attention of synthetic organic chemists.[1] Although stoichiometric amounts of chiral acid were employed initially, [2] a number of enantioselective catalysts such as chiral Lewis acid catalysts [3] and chiral base catalysts [4] have been developed lately. In addition to metal-based chiral catalysts, [5] the use of small organic molecules as catalysts to promote asymmetric reactions has emerged as a new frontier in reaction methodology.[6] Accordingly, l-proline derivatives [7] and peptide derivatives [8] have been developed as catalysts for the Mannich-type reactions. We previously reported that Mannich-type reactions [9] and the aza-Diels-Alder reaction [10] proceed smoothly in the presence of a catalytic amount of a strong Brønsted acid. We thus postulated that the use of a chiral Brønsted acid, in which the proton is surrounded by bulky substituents, may lead to effective asymmetric induction. We report herein an enantioselective Mannich-type reaction of silyl enolates with aldimines catalyzed by a chiral metal-free Brønsted acid. [11,12] First, treatment of aldimine 1 a (Scheme 1, R 1 = Ph) and ketene silyl acetal 2 (3.0 equiv) with 0.3 equivalents of the chiral phosphate 4 a [13,14,15] (which is readily prepared from (R)-BINOL; Scheme 2) in toluene at À78 8C led to a smooth Mannich-type reaction to give 3 a (R 1 = Ph). However, no enantioselectivity was observed (Table 1, entry 1), as deterScheme 1. Mannich-type reaction of aldimines 1 and ketene silyl acetals 2 to form b-aminoesters 3.

An Easy Entry to Optically Active Spiroindolinones: Chiral Brønsted Acid‐Catalysed Pictet–Spengler Reactions of Isatins

“…to obtain the desired compound 4a in 86% enantiomeric excess ( [8][9][10][11]. [13] We found that DMF was the solvent of choice with regard to reactivity and enantioselectivity.…”

“…[4] We started our optimisation (Table 1) by studying the reaction of tryptamine 2a with isatin 3a under the catalysis of several (S)-BINOL derived phosphoric acids 1a-f with different substituents at the 3 and 3' positions (Table 1 entries [1][2][3][4][5][6]. [9,11] THF was chosen as reaction medium to ensure solubilisation of isatin 3a.…”

Enantioselective Cyclopropanation with TADDOL‐Derived Phosphate Ligands

“…[1] Among the growing family of organocatalysts, chiral Brønsted acids have emerged as powerful agents in a number of enantioselective transformations. For example, chiral phosphoric acids derived from BINOL, [2] VAPOL [3] and BINAM [4] have been recently shown to catalyze reactions with excellent enantioselectivities. Recently, we reported an alternative use of BINOL-iodomethylzinc phosphates as a new powerful family for zinc carbenoid-mediated cyclopropanation of alkenes [5] ( Figure 1).…”

Enantioselective Organocatalytic Transfer Hydrogenation of α‐Imino Esters by Utilization of Benzothiazoline as Highly Efficient Reducing Agent

“…We have recently reported that benzothiazoline [8] functioned as a novel reducing agent in the asymmetric transfer hydrogenation of ketimines, [9] giving rise to the corresponding amines with excellent enantioselectivities. As a result of our continuing efforts towards the development of chiral Brønsted acid-catalyzed reactions, [10,11,12] we wish to report herein the phosphoric acid-catalyzed asymmetric transfer hydrogenation of a-imino esters using benzothiazoline as the reducing agent. Preliminary experiments were carried out with the combination of ethyl imino ester 2a and benzothiazoline 4 (Table 1).…”